Cryosurgical fluid supply

ABSTRACT

Improved systems, devices, and methods for delivering cryogenic cooling fluid to cryosurgical probes such as cryosurgical endovascular balloon catheters take advantage of the transients during the initiation and termination of cryogenic fluid flow to moderate the treatment temperatures of tissues engaged by the probe. A flow limiting element along a cryogenic fluid path intermittently interrupts the flow of cooling fluid, often cycling both the fluid flow and treatment temperature. This can maintain the tissue treatment temperature within a predetermined range which is above the treatment temperature provided by a steady flow of cryogenic fluid. In another aspect, room temperature single-use cooling fluid cartridges are filled with a sufficient quantity of cryosurgical fluid to effect a desired endovascular cryosurgical treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation patent application of U.S.patent application Ser. No. 12/652,466, filed Jul. 5, 2012, issued asU.S. Pat. No. 8,333,758 on Dec. 18, 2012, which is a continuation patentapplication of U.S. patent application Ser. No. 11/252,466, filed Oct.17, 2005, issued as U.S. Pat. No. 7,641,679 on Jan. 5, 2010, which is acontinuation patent application of U.S. patent application Ser. No.10/785,503 filed on Feb. 23, 2004, issued as U.S. Pat. No. 6,972,015 onDec. 6, 2005, which is a continuation patent application of U.S. patentapplication Ser. No. 10/105,577 filed Mar. 21, 2002, which issued asU.S. Pat. No. 6,786,901 on Sep. 7, 2004, which is a continuation of U.S.patent application Ser. No. 09/268,205 filed Mar. 15, 1999, which issuedas U.S. Pat. No. 6,432,102 on Aug. 13, 2002, the full disclosures ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to apparatus and methods forcryosurgical therapy. In a particular embodiment, the invention providesa cryosurgical fluid delivery system which makes use of transients inthe cooling cycle to moderate the cooling effects of a cryosurgicalendovascular balloon catheter.

A number of percutaneous intravascular procedures have been developedfor treating atherosclerotic disease in a patient's vasculature. Themost successful of these treatments is percutaneous transluminalangioplasty (PTA). PTA employs a catheter having an expansible distalend (usually in the form of an inflatable balloon) to dilate a stenoticregion in the vasculature to restore adequate blood flow beyond thestenosis. Other procedures for opening stenotic regions includedirectional atherectomy, rotational atherectomy, laser angioplasty,stenting, and the like. While these procedures have gained wideacceptance (either alone or in combination, particularly PTA incombination with stenting), they continue to suffer from significantdisadvantages. A particularly common disadvantage with PTA and otherknown procedures for opening stenotic regions is the subsequentoccurrence of restenosis.

Restenosis refers to the re-narrowing of an artery following aninitially successful angioplasty or other primary treatment. Restenosistypically occurs within weeks or months of the primary procedure, andmay affect up to 50% of all angioplasty patients to some extent.Restenosis results at least in part from smooth muscle cellproliferation in response to the injury caused by the primary treatment.This cell proliferation is referred to as “hyperplasia.” Blood vesselsin which significant restenosis occurs will typically require furthertreatment.

A number of strategies have been proposed to treat hyperplasia andreduce restenosis. Previously proposed strategies include prolongedballoon inflation, treatment of the blood vessel with a heated balloon,treatment of the blood vessel with radiation, the administration ofanti-thrombotic drugs following the primary treatment, stenting of theregion following the primary treatment, and the like. While theseproposals have enjoyed varying levels of success, no one of theseprocedures is proven to be entirely successful in avoiding alloccurrences of restenosis and hyperplasia.

It has recently been proposed to prevent or slow reclosure of a lesionfollowing angioplasty by remodeling the lesion using a combination ofdilation and cryogenic cooling. Co-pending U.S. patent application Ser.No. 09/203,011 filed Dec. 1, 1998, the full disclosure of which isincorporated herein by reference, describes an exemplary structure andmethod for inhibiting restenosis using a cryogenically cooled balloon.While these proposals appear promising, the described structures andmethods for carrying out endovascular cryogenic cooling would benefitfrom still further improvements. For example, the mechanical strength ofthe vasculature generally requires quite a high pressure to dilate thevessel during conventional angioplasty. Conventional angioplasty ofteninvolves the inflation of an angioplasty balloon with a pressure ofroughly 10 bar. These relatively high pressures can be safely usedwithin the body when balloons are inflated with a benign liquid such ascontrast or saline. However, high pressures involve some risk ofsignificant injury should the balloon fail to contain a cryogenic gas orliquid/gas combination at these high pressures. Additionally, work inconnection with the present invention has shown that theantiproliferative efficacy of endoluminal cryogenic systems can be quitesensitive to the temperature to which the tissues are cooled: althoughcommercially available, cryogenic cooling fluids show great promise forendovascular use, it can be challenging to reproducibly effectcontrolled cooling without having to resort to complex, high pressure,tight tolerance, and/or expensive cryogenic control components.

For these reasons, it would be desirable to provide improved devices,systems and methods for effecting cryosurgical and/or other lowtemperature therapies. It would further be desirable if these improvedtechniques were capable of delivering cryosurgical cooling fluids intothe recently proposed endovascular cryosurgical balloon catheters, aswell as other known cryosurgical probes. It would be particularlydesirable if these improved techniques delivered the cryosurgicalcooling fluid in a safe and controlled manner so as to avoid injury toadjacent tissues, ideally without requiring a complex control systemand/or relying entirely on the operator's skill to monitor and controlthese temperature-sensitive treatments.

2. Description of the Background Art

A cryoplasty device and method are described in WO 98/38934. Ballooncatheters for intravascular cooling or heating of a patient aredescribed in U.S. Pat. No. 5,486,208 and WO 91/05528. A cryosurgicalprobe with an inflatable bladder for performing intrauterine ablation isdescribed in U.S. Pat. No. 5,501,681. Cryosurgical probes relying onJoule-Thomson cooling are described in U.S. Pat. Nos. 5,275,595;5,190,539; 5,147,355; 5,078,713; and 3,901,241. Catheters with heatedballoons for post-angioplasty and other treatments are described in U.S.Pat. Nos. 5,196,024; 5,191,883; 5,151,100; 5,106,360; 5,092,841;5,041,089; 5,019,075; and 4,754,752. Cryogenic fluid sources aredescribed in U.S. Pat. Nos. 5,644,502; 5,617,739; and 4,336,691. Thefollowing U.S. patents may also be relevant to the present invention:U.S. Pat. Nos. 5,458,612; 5,545,195; and 5,733,280.

The full disclosures of each of the above U.S. patents are incorporatedby reference.

SUMMARY OF THE INVENTION

The present invention generally overcomes the advantages of the priorart by providing improved systems, devices, and methods for deliveringcryogenic cooling fluid to cryosurgical probes, such as the newcryosurgical endovascular balloon catheters. The invention generallytakes advantage of the transients during the initiation and terminationof cryogenic fluid flow to moderate the treatment temperatures oftissues engaged by the probe. In some embodiments, a flow limitingelement along a cryogenic fluid path intermittently interrupts the flowof cooling fluid, often cycling both the fluid flow and treatmenttemperature. This can help maintain the tissue treatment temperaturewithin a predetermined range which is significantly above the treatmenttemperature which would be provided by a steady flow of cryogenic fluid.This intermittent flow may decrease sensitivity of the system to theparticular configuration of the exhaust gas of flow path defined by aflexible catheter body disposed within the vascular system. Cooling ofthe vessel along the catheter body proximally of a balloon may also bedecreased, thereby avoiding the embolization of frozen blood within thevasculature. In another aspect, the invention makes use of a single-usecooling fluid cartridges which may be transported safely at roomtemperature when filled with a sufficient quantity of cryosurgical fluidto effect a desired treatment, and which can be safely andcost-effectively disposed of after use.

In a first aspect, the invention provides a cryogenic fluid deliverysystem for use with a cryogenic probe having a cryogenic fluid input anda cooling surface for engaging a target tissue. The cryogenic deliverysystem comprises a cooling fluid container having a cryogenic fluidoutput. A cooling fluid path couples the fluid output of the containerto the fluid input of the probe. A flow interrupter disposed along thecooling fluid path intermittently inhibits the flow of cryogenic coolingfluid from the container to the probe so as to limit cooling by thecooling surface.

A variety of flow interrupter structures may be used to moderate coolingof the target tissue. For example, the flow interrupter may comprise asolenoid valve, which will often be driven by a simple intermittenttiming switch, a timing circuit, or the like. Alternatively, the flowinterrupter may comprise a valve member rotatably engaging a valve bodyso as to provide fluid communication when the valve member is in a firstrotational position and inhibit fluid communication when the valve is ina second rotational position. Such a rotatable valve assembly will oftenbe driven by a motor, such as an electric motor, a pneumatic motor, orthe like. Still further alternative fluid interrupters may comprise adeformable cryogenic conduit which can be occluded by actuation of asolenoid, pneumatic ram, or the like.

In another aspect, the invention provides a cryogenic fluid deliverysystem for use with a cryogenic probe. The probe has a cryogenic fluidinput and a cooling surface, and the delivery system includes a coolingfluid container having a cryogenic fluid output. A cryogenic coolingfluid is disposed in the fluid container, and a cooling fluid pathcouples the fluid output of the container to the fluid input of theprobe. Means are disposed along the cooling fluid path for limitingcooling of the cooled surface by intermittently inhibiting cooling fluidflow from the container to the probe.

In another aspect, the invention provides a single-use cryogenic fluiddelivery system for use with a cryogenic endovascular catheter so as toinhibit hyperplasia of a diseased blood vessel region of a patient body.The cryogenic delivery system comprises a cooling fluid container and aconnector for coupling to the catheter. A cooling fluid path providesfluid communication from the container to the connector. The path has aseal, and a cryogenic cooling fluid is disposed within the fluidcontainer. The cooling fluid has a quantity and is at a pressure suchthat the catheter will cool the blood vessel to a temperature in apredetermined temperature range so as to inhibit hyperplasia when theconnector is coupled to the catheter and the seal is opened.

Advantageously, the cryogenic fluid may be stored and transported at thedesired pressure by the container when the container is at roomtemperature. The quantity of cryogenic fluid may be sufficient tomaintain the blood vessel within the treatment temperature range for atime in predetermined treatment time range, thereby allowing the coolingsystem to be substantially self-controlling. Such a system isparticularly useful for inhibiting hyperplasia or neoplasia, thequantity and pressure of the cryogenic fluid ideally being sufficient tocool a surface of the diseased blood vessel region to a temperature fromabout −5.degree. C. to about −25.degree. C. for a time from about 10 toabout 60 seconds, most often for a time between about 20 and 30 seconds.

The container will often comprise a disposable cartridge having afrangible seal. The seal may be breached by a fitting which threadablyengages a casing in which the container is received. Such disposablecartridges can safely maintain cryosurgical cooling fluids such asN.sub.2O at high pressures and in sufficient quantities to effect avariety of desired treatments. For example, the cartridge may containabout 5 to 30 grams of cooling fluid, and may contain N.sub.2O or othercooling fluids at a pressure between about 400 and 1000 psi.

In a method aspect of the present invention, a tissue of a patient bodycan be treated using a cooling surface of a cryosurgical probe. Such amethod may comprise coupling a cryogenic fluid canister to the probe,the canister containing a pressurized cryogenic cooling fluid. Thecooling fluid flows from the canister toward the cooling surface of theprobe. The flow is intermittently interrupted to limit cooling of thetissue by the probe.

The interruption periodically inhibits the flow of cooling fluid toavoid cooling of a tissue below a predetermined temperature range. Thiscan repeatedly cycle a tissue temperature, ideally reaching atemperature within a range from about −5.degree. C. to about −25.degree.C. for a time in a range from about 10 to about 60 seconds during thecycle, most often for a time between about 20 and 30 seconds. Typically,the cycling of the flow interruption and/or tissue temperature will havea period in a range from about 0.01 second to about 5 seconds, thefrequency ideally being in a range from about 0.3 to about 3 hertz.

While this summary describes many of the optional, preferred features ofthe exemplary embodiments, it should be understood that the invention isnot limited to these specific embodiments. A fuller understanding of thespecific embodiments and their operation can be obtained with referenceto the drawings and description which follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a cryogenic/angioplasty ballooncatheter system including a cryogenic fluid supply system according tothe principles of the present invention.

FIG. 2 is an exploded cross-sectional view of a cryogenic fluid supplysystem for use in the cryosurgical system of FIG. 1.

FIGS. 3A-3C schematically illustrate alternative flow interrupters formoderating the treatment temperatures of a cryosurgical system.

FIG. 4 illustrates cryogenic cooling temperatures provided by expansionof N.sub.2O.

FIGS. 5A-5C graphically illustrate theoretical and measured treatmenttemperatures provided by an endovascular cryogenic balloon cathetersystem including the cryogenic fluid supply of the present invention.

FIGS. 6A-6C are partial cross-sections schematically illustrating themethod of the present invention for inhibition of hyperplasia.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The devices, systems, and methods of the present invention are relatedto co-pending U.S. patent application Ser. No. 09/203,011, filed on Dec.1, 1998 for an Apparatus and Method for Cryogenic Inhibition ofHyperplasia, and to co-pending U.S. patent application Ser. No.60/121,638, filed Feb. 24, 1999 for a Cryogenic Angioplasty Catheter.These applications are assigned to the present assignee, and their fulldisclosures are incorporated herein by reference.

Referring now to FIG. 1, an exemplary system 10 is capable of treating adiseased vessel wall of a blood vessel using a combination of bothangioplasty dilation and cryogenic cooling. In general, system 10includes a catheter 12 coupled to a cryogenic fluid supply system 14 andan angioplasty pressurization system 16. One or both of cryogenic system14 and pressurization system 16 may optionally be operatively coupled toa controller 18 for coordination of cooling and dilation. In someembodiments, controller 18 may actively control cryogenic cooling bymodulating cooling fluid supply rates, cooling exhaust gas portpressures, cycling of the cooling fluid flow, or the like, in responseto balloon pressure, measured temperature, or the like. In otherembodiments, the system will be substantially self-modulating throughthe use of predetermined supply quantities, pressures, and/or flowcycling rates.

Catheter 12 generally includes a catheter body having a proximal end 22and a distal end 24. A proximal housing 26 includes a number of portsfor coupling of cryogenic supply system 14, pressurization system 16,and the like, to the proximal end of the catheter body. An angioplastyballoon 28 and a cryogenic balloon 30 are mounted near the distal end ofcatheter body 24. A catheter body will generally be flexible and containa plurality of lumens to provide fluid communication between the portsof proximal housing 26 and balloons 28 and 30.

Angioplasty balloon 28 may be formed from a variety of materialsconventionally used for dilating blood vessels. Angioplasty balloon 28will typically comprise a non-distensible material such as polyethyleneterephthalate (PET). Such angioplasty balloons are formed in a varietyof sizes depending on their intended use, typically having a length andrange from about 15 mm to about 50 mm and an expanded diameter in arange from about 2 mm to about 10 mm. Prior to inflation, angioplastyballoon 28 will generally remain in a low profile configuration suitablefor insertion into and maneuvering through the vascular system. Aguidewire lumen 32 extends through angioplasty balloon 28 and cryogenicballoon 30 from a proximal guidewire port 34 to facilitate accessing thetarget treatment site.

High contrast markers may be provided within balloon 30 to enhance animage of the distal end of the catheter and facilitate positioning ofthe balloon fluoroscopically, sonographically, or under any otheralternative image modality (with appropriate contrast structures). Suchmarkers may be formed by winding a gold or platinum wire around thetubular structure defining a pressurization lumen 36. Angioplastyballoon 28 is inflated by injecting contrast fluid 40 frompressurization system 16 into pressurization lumen 36 through apressurization port 38. In this embodiment, balloon 28 is isolated fromballoon 30, so as to avoid inadvertent inflation of the cryogenicballoon during dilation.

In the catheter illustrated in FIG. 1, cryogenic balloon 30 is nestedwithin the angioplasty balloon 28. It should be understood thatcryogenic balloon 30 may alternatively be axially displaced from thecryogenic balloon, or that a single balloon may function as both thecryogenic cooling and dilation. Cooling may be provided by containingthe cryogenic cooling fluid within a rigid heat exchanger, andoptionally cooling a surrounding balloon wall via a fluid having apredetermined freezing temperature. In still further alternativeembodiments, cryogenic cooling catheters may be provided withoutdilation capabilities. Still further alternative cooling probes mightbenefit from the modulated cooling of the present invention, includinghand-held probes connected to cooling surfaces by rigid shafts. In otherwords, many probe structures might benefit from the present invention.It should be understood that the supply system need not be separate orseparable from the probe.

Regardless of the specific structure of the cooling surface, cryogenicfluid 60 is generally directed from an output of cryogenic fluid supply14 to an input of the cooling probe. In the embodiment of FIG. 1, thecryogenic fluid is injected into a cryogenic supply port 42 and passestoward cryogenic balloon 30 through cryogenic supply lumen 44 withincatheter body 20. Cryogenic fluid 60 may comprise cryogenic liquids orliquid/gas mixtures, optionally including carbon dioxide (CO.sub.2),nitrous oxide (N.sub.2O), liquid nitrogen (N.sub.2), a fluorocarbon suchas AZ-50™ (sold by Genetron of Morristown, N.J.), or the like. Ascryogenic liquid 60 passes from the supply lumen and into cryogenicballoon 30, it may be distributed both radially and axially by adiffuser 46. Diffuser 46 will generally comprise a tubular structurewith radially oriented openings. As the openings are radially oriented,diffuser 46 will direct the cooling fluid roughly perpendicularly towardthe wall of cryogenic balloon 30, so that the heat transfer coefficientbetween the cooling vapor and balloon wall is quite even and quite high.This helps to reduce the temperature of the balloon wall, and providesgreater heat extraction for a given flow rate of coolant. Additionally,as the ports are distributed both circumferentially and axially alongthe balloon, the diffuser can provide a substantially uniform coolingover a significant portion of (often over the majority of) the surfaceof the balloon.

In some embodiments, the cryogenic cooling fluid may pass through aJoule-Thompson orifice between fluid supply lumen 44 and balloon 30. Inother embodiments, at least a portion of the cryogenic cooling fluid mayexit one or more ports into the balloon as a liquid. The liquid willvaporize within the balloon, and the enthalpy of vaporization can helpcool the surrounding vessel wall. The liquid may coat at least a portionof the balloon wall so as to enhance even cooling over at least aportion of the vessel wall. Hence, the ports of diffuser 46 may have atotal cross-section which is smaller than a cross-section of the fluidsupply lumen 44, or which is at least as large as (or larger than) thecross-section of the fluid supply lumen.

After the cryogenic cooling fluid vaporizes within balloon 30, itescapes the balloon proximally along an exhaust lumen 48, and isexhausted from catheter 12 through an exhaust port 50. Inflation ofcryogenic balloon 30 may be controlled by the amount of cryogenic fluidinjected into the balloon, and/or by the pressure head loss experiencedby the exhaust gases. Cooling is generally enhanced by minimizing thepressure within balloon 30. To take advantage of this effect so as tocontrol the amount of cooling, a fixed or variable orifice may beprovided at exhaust port 50. Alternatively, a vacuum might be applied tothe exhaust port to control cooling and enhance cooling efficiency. Insome embodiments, a layer of insulting material 72 may be disposedbetween the cryogenic cooling fluid and the tissue engaging surface ofthe balloon. A suitable insulation material might include a thin layerof expanded Teflon™ (ePTFE) on an inner or outer surface of cryogenicballoon 30, on an inner or outer surface of angioplasty balloon 28, orthe like. A wide variety of alternative insulation materials might alsobe used.

To accurately control and/or monitor the pressure within cryogenicballoon 30, proximal housing 26 may include a cooling balloon pressuremonitoring port 56. The pressure monitoring port will be in fluidcommunication with the cryogenic balloon 30, preferably through adedicated pressure monitoring lumen (not shown). Signals from pressuremonitoring port 56 and a thermocouple connector 58 may be transmitted tothe controller 18.

In use, the nested cryogenic/angioplasty balloon catheter of FIG. 1 mayallow pre-cooling of a diseased vessel wall prior to dilation, coolingof a vessel wall after dilation, interspersed cooling/dilation, and evenconcurrent dilation during cooling. In some endovascular therapies,cooling without dilation may be desired, so that no provisions forinflation of an angioplasty balloon 28 by contrast 40 are required.

Cryogenic fluid delivery system 14 is illustrated in FIG. 2. Deliverysystem 14 makes use of a disposable cartridge 102 containing a cryogenicfluid 104. Cartridge 102 is received in a casing 106, and the casingthreadably engages a fitting 108. By placing cartridge 102 in casing 106and threading fitting 108 to the casing, a frangible seal 110 of thecartridge can be breached by a protruding tube 112 of the fitting.Fitting 108 may include a sealing body such as a rubber washer 114 toavoid leakage of cooling fluid 104, while the fitting and casing 106 mayinclude gripping surfaces to facilitate breaching seal 110.

Once seal 110 has been breached by fitting 108, cryogenic cooling fluid104 passes through a lumen 116 through the fitting and on toward theballoon surface. Coupling of fluid delivery system 14 tocooling/angioplasty balloon catheter 12 is facilitated by including adetachable connector 118 along the cooling fluid flow path, theconnector typically comprising a luer fitting which sealingly engagesfluid supply port 42 of the catheter. While connector 118 is here shownclosely coupled to fitting 108, it should be understood that the fluidflow path may follow a longer, and optionally flexible path. In fact,aspects of the present invention will find uses with standard reusablecryogenic fluid supply system.

In fluid delivery system 14 illustrated in FIG. 2, a simple stopcock 120is disposed between fitting 108 and connector 118. Stopcock 120 allowsthe cryogenic system operator to pierce seal 110 of cartridge 102 whilesetting up the system, and to later manually initiate flow of thecooling fluid by turning a lever of the stopcock. A port on stopcock 120may be in fluid communication with the open cooling fluid path to verifycooling fluid pressure, temperature, or the like. Alternatively, thestopcock port may be isolated from the cooling fluid path when thestopcock opens.

Casing 106 and fitting 108 may comprise a variety of polymer and/ormetallic materials. In the exemplary embodiment, casing 106 and at leasta portion of fitting 108 are off-the-shelf items sized and adapted toreceive and open a standard, commercially available pressurized fluidcartridge. The casing and seal opening components of the fitting may befabricated by assembling and/or modifying components sold commerciallyby iSi Gmbh located in Vienna, Austria.

Cartridge 102 may be transported, stored, and optionally, used at roomtemperature. The cryogenic cooling fluid sealed within cartridge 102 maycomprise CO.sub.2, N.sub.2O, AZ-50™ fluorocarbon, and/or a variety ofalternative cryogenic cooling fluids. As these fluids are at quite highpressures within cartridge 102, they may be in the form of a liquid orgas/liquid mixture, even at room temperature. The pressure of coolingfluid 104 within cartridge 102 will often be greater than 400 psi,preferably being about 500 psi or more at room temperature. It should beunderstood that the cartridge pressure will decreased during thetreatment as cooling fluid is consumed.

Advantageously, the quantity of cooling fluid 104 may be such that thecryosurgical system (including cryogenic fluid supply 14 and catheter12) cool and maintain a target tissue within a predetermined temperaturerange for a time within a predetermined time range by the time thecooling fluid is consumed from the canister. In other words, byselecting the proper fluid supply cartridge and catheter structures, thecryogenic therapy may be self-terminating without active intervention byan electronic control system, the operator, or the like. Cooling flowmay cease when the fluid pressure within cartridge 102 is equal toambient pressure, or may optionally be interrupted when the pressuredrops below some threshold value.

Canister 102 will typically comprise a metallic structure. Suitablecartridges will hold quantities of cryogenic cooling fluid that aresufficient to cool the target tissue to the treatment temperature rangefor a time in the predetermined time range. Cartridges might havevolumes between 2 cc and 100 cc (depending in part on the flashexpansion temperatures of the cryogenic fluid), and may contain betweenabout 5 g and 30 g of cooling fluid. A typical cartridge might contain aquantity of N.sub.2O in a range from about 5 ml to about 20 ml, ideallyhaving about a 10 ml or 8 grams of N.sub.2O liquid at about 750 psi.Conveniently, such cartridges are commercially available for use inwhipped cream dispensers. As explained below, canister 102 may be atroom temperature or even chilled, but will preferably be warmed gentlyprior to use.

Although the above discussion occasionally refers to structures andtechniques for enhancing the efficiency of cryogenic cooling, knowncryogenic cooling techniques are capable of inducing temperatures wellbelow the preferred treatment temperature ranges for use with thepresent invention. To moderate the cooling of the target tissue andprovide antiproliferative benefits, the systems of the present inventionmay optionally rely on thermal insulation 72, as described above withreference to FIG. 1. Alternatively, a motor 122 may drivingly engagestopcock 120 so as to intermittently interrupt the flow of cooling fluidto the balloon. By cycling of the cooling fluid flow on and off, thepresent invention takes advantage of the thermal transients of thecooling system to prevent the tissue from reaching the low temperaturesassociated with a steady state cooling flow.

A variety of structures might be used to intermittently interrupt theflow of cooling fluid to the cryosurgical probe. In the embodiment ofFIG. 2, an output shaft of an electrical motor assembly might beattached to a modified commercially available medical stopcock valve.Suitable motors might be powered from a standard wall outlet orbatteries, and a reduction drive unit might be used to reduce the speedof the stopcock valve rotation to about one cycle per second. The drivemotor may have a fixed speed to provide a temperature within a singlepredetermined temperature range, or may have a variable speed toactively control the temperature by varying the cycle speed, to alterthe predetermined treatment temperature range for a particulartreatment, and/or to provide the predetermined temperature range given aparticular ambient condition, cryosurgical probe configuration, and thelike.

Referring now to FIGS. 3A through C, alternative cooling fluidinterrupters 124 may comprise a solenoid valve 126 coupled to a timer128. Solenoid valve 126 will preferably have a relatively low (dead)space, and will generally have a non-metallic body. Timer 128 maycomprise an electro-mechanical timer, a circuit (such as an R-C timingcircuit), or the like. Fabricating the solenoid valve body of anon-metallic material can help avoid the conduction of energy out of thesystem. Minimizing dead space in the flow path of the valve helps thevalve from acting as an expansion chamber, which might otherwise robenergy from the system.

Referring now to FIG. 3B, a motor-driven rotating valve provides fluidcommunication from cartridge 102 to balloon 30 when a passage of thevalve member 130 is aligned with a passage of the valve body 132, andblocks flow when the passage of the valve member is blocked by the valvebody. This is the general case of the motor driven stopcock illustratedin FIG. 2. A variety of valve passage configurations might be used toprovide multiple flow cycles per rotation of valve member 130. Forexample, the valve member may include a pair of orthogonal passages inan “X” configuration, thereby providing four flow cycles per rotation ofthe valve member. Flow can further be modified by changing the diameterof the passage or passages within valve member 130, the configuration ofpassages in valve body 132, the speed of rotation of the valve, and thelike. Advantageously, a variety of flow cycles can be achieved.

Referring now to FIG. 3C, cooling fluid flow may alternatively be pulsedby intermittently impinging on a deformable cooling flow conduit 134.Suitable conduits might include a polyamide tube having an innerdiameter in a range from about 0.012″ to about 0.035″ with a relativelythick tubal wall. An exemplary deformable conduit comprises a polyamidetube having an inner diameter of 0.016″ and a relatively thick wall ofabout 0.0015″, and also having a PTFE lining of about 0.0005″.

Deformable conduit 134 may be pinched between a flat plate 136 andsolenoid 138. Suitable small solenoids may be battery powered, and mayoptionally include a mechanical advantage mechanism to provide enoughforce to substantially or entirely occlude the cooling flow.Alternatively, a pressurized cylinder/piston arrangement might be used,thereby providing significantly higher forces for a given size. Such apneumatic cylinder may be powered by any source of pressurized fluid,including an external pressurized air source, cartridge 102, or thelike. Regardless of the specific pinch actuator, cycling of the flowcycle may again be provided by a timer 128, which may comprise anelectromechanical timer, an R-C circuit, a mechanical or pressureactuated timing mechanism, or the like. It should be understood that thetimer may be incorporated into the pinch actuation mechanism.

The benefits from the use of a flow interrupter can be understood withreference to FIGS. 4 and 5A through C. If cartridge 102 containsN.sub.2O at 750 psi, and if the cartridge is placed in an ice bath(thereby providing a convenient and reproducible initial condition),flash expansion of the cooling fluid to a pressure between atmospheric(14.7 psi) and 100 psi will result in cryogenic fluid temperatures in arange from about −45.degree. C. to about −90.degree. C. Such lowtemperatures are useful, for example, for therapies in which cryogenicablation of tissues is desired. Surprisingly, it may be beneficial togently warm the cartridge to enhance the fluid pressure and coolingsystem performance. Hence, alternative predetermined initial conditionsmight be provided by warming canister 102, preferably to about bodytemperature (with a hot plate, water bath, or the like) or even byholding the canister in a person's pocket (which may warm the canisterto about 33.degree. C.). Still further predetermined initialtemperatures may simply comprise operating room temperature.

To provide apoptosis and/or programmed cell death so as to inhibithyperplasia and/or neoplasia of a blood vessel related to angioplasty,stenting, rotational or directional atherectomy, or the like, it willoften be desirable to provide more moderate cryogenic treatmenttemperatures. A wide variety of other therapies may also benefit fromthese treatment temperatures, including the formation of cryogeniclesions within the coronary atrium for treatment of atrial fibrillation,and the like. As a particular example, the cardiac tissue ablationdevices and methods described in PCT Patent Application WO 98/49957,published on Nov. 12, 1998 (the full disclosure of which is incorporatedherein by reference) might benefit from treatment temperaturessignificantly higher than about −30.degree. C., in other words,significantly warmer than cooled tissue temperatures provided by manycryosurgical methods.

Referring now to FIG. 5A, manually opening stopcock 120 of cryogenicfluid supply system 14 illustrated in FIG. 2 will typically result in asteady state flow of cooling fluid to balloon 30, resulting in a tissuetemperature profile which quickly (often in about 2 seconds or less)drops down to a temperature of about −30.degree. C. or less. Engagedblood vessel region will remain at this low temperature until coolingfluid 104 is fully consumed. Such cold treatment temperatures may inducenecrosis, or may possibly be moderated by providing an insulationmaterial between the cooling fluid and the engaged tissue, by narrowingthe exhaust gas port so as to raise the pressure within balloon 30, orthe like. The limited quantity of cooling fluid in cartridge 102 limitsthe treatment time without requiring active intervention by the surgeon.

Referring now to FIG. 5B, cryogenic treatment temperatures can bemodulated by intermittently cycling fluid flow. Specifically, flow isreduced and/or stopped significantly before the tissue reaches the nadirtemperature. At this point, the body will absorb energy out of thesystem, raising the temperature of the treatment tissue. The interruptermay cycle the flow on and off to keep the system at a relatively stabletemperature for the duration of treatment. Ideally, the on and offcycling can be controlled by a simple fixed timer so as to reach atemperature between about −5.degree. C. and about −25.degree. C. duringeach cycle. In the exemplary embodiment, the tissue is maintained withina temperature range from about −5.degree. C. to about −25.degree. C.throughout at least some of, and often most of, the thermal cycles. Insome embodiments, a temperature feedback mechanism may be employed tomodify the cooling cycles by altering a drive signal provided fromcontroller 18 to the interrupter.

Referring now to FIG. 5C, a cryogenic cooling balloon having a diameterof about 2.5 mm and a length of about 4 cm was cooled by a N.sub.2Ocartridge having a volume of about 10 cc. The cartridge was at aboutbody temperature when flow began, providing a pressure of about 750 psi.A stopcock disposed along the flow path between cartridge 102 andballoon 30 was rotated at a speed of about one rotation per second by anelectric motor. Balloon 30 was placed in body temperature water in thisbenchtop experiment, and temperatures were measured at an outer surfaceof the balloon. These experiments produced the treatment temperaturesshown in these two different experimental cooling runs.

A method for using the modulated temperature cryogenic system 10 isillustrated in FIGS. 6A-6C. Typically, catheter 12 is introduced intothe vasculature through an introducer sheath, most often using thewidely known Seldinger technique. A guidewire GW is maneuvered throughthe vessel, and catheter 12 is advanced over the guidewire andpositioned adjacent diseased portion DP a vessel wall VW.

Once balloon 30 is in position, the balloon can be inflated in aconventional manner to dilate the vessel, as illustrated in FIG. 6B. Ascan be understood with reference to FIG. 10, dilation may occur using anouter angioplasty balloon using conventional contrast fluid 40 tofacilitate fluoroscopically directing a dilation procedure.Alternatively, the vessel may be dilated using a separate angioplastycatheter, an axially displaced angioplasty balloon, or using thecryogenic balloon itself. In still further alternatives, cryogeniccooling may be initiated prior to or during dilation. Regardless,cooling will preferably be effected by coupling a disposable cartridgeto balloon 30 so that a cryogenic cooling fluid contained within thecartridge is transmitted to the balloon. Cooling flow between thecartridge and balloon 30 will be interrupted intermittently so as tomodulate the treatment temperature, so that a surface layer 88 of vesselwall VW thermally engaged by balloon 30 cycles within a treatmenttemperature range from about −5.degree. C. to about −25.degree. C. for atime in a range from about 10 to about 60 seconds. As a result, thistreated tissue layer undergoes apoptosis, thereby avoiding and/orreducing the proliferative response of the luminal wall to dilation.

As can also be understood with reference to FIGS. 6A-6C, plaque P orother occlusive matter may coat a portion of the vessel's lumen L. Totreat the vessel wall tissues lining lumen L at the desired treatmenttemperature, balloon 30 may be cooled so that an outer surface of theballoon has a temperature significantly below the desired tissuetreatment temperature range. Specifically, balloon 30 may be cooled tohave an outer surface temperature selected to compensate for a thicknessof occlusive matter disposed between the balloon surface and the targetvessel tissue, with the selected balloon temperature typicallydecreasing with increasing occlusive matter thickness. The thickness ofthe occlusive matter may be measured in a blood vessel using a varietyof techniques, including intravascular ultrasound (IVUS), fluoroscopy,and the like.

While the exemplary embodiments have been described in some detail, byway of example and for clarity of understanding, a variety ofmodifications, changes, and adaptations will be obvious to those ofskill in the art. For example, a variety of endovascular therapies maybenefit from the antiproliferative effects of the present invention,including angioplasty, stenting, directional and rotational atherectomy,and the like. Alternative treatment probes may also benefit from themoderated cryogenic treatment temperatures provided by the interruptedcooling fluid flow described hereinabove, including open surgicalprocedures effected by manipulating a hand-held rigid cryosurgical probeshaft supplied from conveniently cryosurgical fluid supply systems.Where ablation of a tissue most easily accessed through the vasculatureis desired, the use of a disposable cartridge in combination with aflexible endovascular catheter may allow lesions having a predeterminedsize to be formed, with the total amount of cooling limited by theamount of cryogenic cooling fluid available within the cartridge. Hence,the scope of the present invention is limited solely by the appendedclaims.

The invention claimed is:
 1. A catheter comprising: a first lumen; asecond lumen; an outer balloon defining an outer balloon chamber influid communication with the first lumen; an inner balloon positionedinside the outer balloon chamber, the inner balloon defining an innerballoon chamber in fluid communication with the second lumen, the innerballoon chamber being smaller than the outer balloon chamber, the innerballoon chamber being a cooling chamber.
 2. The catheter of claim 1,further comprising a guidewire lumen extending through the innerballoon.
 3. The catheter of claim 1, further comprising one or moreports configured to deliver a cooling fluid from the second lumen to theinner balloon.
 4. The catheter of claim 3, wherein the one or more portsare radially oriented openings of a diffuser positioned inside the innerballoon chamber.
 5. The catheter of claim 1, further comprising a thirdlumen in fluid communication with the inner balloon, wherein the secondlumen is an inflow lumen for fluid to enter the inner balloon chamberand the third lumen in an outflow lumen for fluid to exit the innerballoon chamber.
 6. The catheter of claim 5, further comprising aproximal housing, the proximal housing comprising: a first port in fluidcommunication with the first lumen; a second port in fluid communicationwith the second lumen; a third port in fluid communication with thethird lumen.
 7. The catheter of claim 6, the housing further comprisinga guidewire port for a guidewire lumen.
 8. The catheter of claim 6, thehousing further comprising a thermocouple connector.
 9. The catheter ofclaim 1, further comprising a temperature feedback mechanism.
 10. Thecatheter of claim 1, further comprising a layer of insulating materialon a surface of either the outer balloon or the inner balloon, thesurface being either an inner surface or an outer surface.
 11. Thecatheter of claim 6, wherein a coolant source is connected to, and influid communication with, the second port of the catheter by adetachable connector.
 12. The catheter of claim 11, wherein a fluidinterrupter is positioned between the coolant source and the detachableconnector, the fluid interrupter configured to interrupt a flow ofcoolant from the coolant source to the catheter.
 13. The catheter ofclaim 12, wherein the fluid interrupter is a stopcock.
 14. The catheterof claim 13, wherein a motor is drivingly engaged to the stopcock so asto intermittently interrupt a flow of coolant from the coolant source tothe catheter.
 15. The catheter of claim 12, wherein the fluidinterrupter is a solenoid valve coupled to a timer.
 16. The catheter ofclaim 12, wherein the fluid interrupter is a motor-driven rotatingvalve.
 17. The catheter of claim 12, wherein the fluid interruptercomprises a solenoid, a flat plate, wherein a deformable conduitextending between the coolant source and the detachable connector ispositioned between the solenoid and the flat plate for intermittentocclusion of the deformable conduit by the solenoid and the flat plate.18. The catheter of claim 17, wherein a timer provides for theintermittent occlusion of the deformable conduit by the solenoid and theflat plate.